DID - March 12, 2009 Issue

Will Margaret Hamburg Lead the FDA?

If Margaret Hamburg is President Barack Obama’s nominee for FDA
commissioner and confirmed by the Senate, she will have a number of safety,
legal and ethics issues to tackle at the agency.

The past 12 months have seen congressional and media criticism of
the agency’s oversight of drug imports and marketing, its administration of
financial ties between industry and FDA advisory committee members, and its
espousal of federal preemption of state tort laws regarding drug labeling.

Hamburg, reportedly Obama’s choice to head the agency, is a
physician who graduated from Harvard Medical School and later performed research
in neuroscience at Rockefeller University in New York from 1985 to 1986 and in
neuropharmacology — the study of how drugs affect the nervous system — at the
National Institute of Mental Health in Bethesda, Md., according to her resume
from the National Institutes of Health.

She was New York City’s health commissioner from 1991 to 1997,
where she developed innovative programs for controlling the spread of
tuberculosis and AIDS, according to the resume.

If nominated, the next step for Hamburg could be hearings in the
Senate Health, Education, Labor and Pensions Committee, followed by a
confirmation vote in the Senate.

Sharfstein as Deputy

Obama also reportedly has chosen Joshua Sharfstein, Baltimore’s
Commissioner of Health since 2005, to become the FDA’s deputy director.

Sharfstein also is a physician who attended Harvard Medical
School. He has “led efforts to improve oversight of children’s cough-and-cold
medications, … increase immunization of healthcare workers, and expand access to
substance abuse treatment with buprenorphine,” according to his resume on
Baltimore’s health department website.

Drug Marketing

Numerous issues pursued by Congress and the media are likely to
occupy the FDA commissioner and the agency’s top staff. Drugmakers’ marketing
practices, such as Merck and Schering-Plough’s campaign for Vytorin, have come
under investigation from dozens of state attorneys general (DID,
Nov.
5, 2008).

Direct-to-consumer marketing has continued to draw congressional
and FDA attention. For example, last October the FDA sent Bayer a warning letter
over two TV ads for its contraceptive Yaz (drospirenone/ethinyl estradiol) that
the agency said broadened its indication, overstated its efficacy and minimized
serious risks (DID,
Oct.
8, 2008).

Conflicts of Interest

Congress also has investigated the influence of drugmakers on the
FDA’s advisory committee process. Rep. Maurice Hinchey (D-N.Y.), a member of the
House Agriculture, Rural Development, Food and Drug Administration and Related
Agencies subcommittee, which is responsible for the FDA’s annual budget, has
asked CDER Director Janet Woodcock to explain the agency’s decision to withdraw
an invitation to Sanjay Kaul to serve as a member of an advisory committee that
discussed Eli Lilly’s blood thinner prasugrel, about which he had expressed
reservations (DID,
Feb.
27).

The recent Wyeth v. Levine decision by the Supreme Court
may change the agency’s previously announced policy on the way that drugmakers
may make changes to physician labeling (DID,
March
5). The court ruled against federal preemption of state drug-labeling laws.

Under a rule that took effect Sept. 22, 2008, manufacturers can
add or strengthen the contraindications, warnings, precautions or adverse
reactions sections of labeling via a supplement called changes being effective
without prior FDA approval, according to the decision. — David Grant

Rep. Waxman Introduces Biogenerics Legislation

Legislation creating a pathway for the FDA to approve generic biologics and
granting innovator companies five years of marketing exclusivity for medicines
was introduced in the House.

The bill, H.R. 1427, creates a pathway for both biosimilars and biogenerics,
and gives innovators as much as a year of additional exclusivity for new
indications and when pediatric studies are conducted. Unlike the Hatch-Waxman
Act, the new legislation does not include provisions for 30-month stays of FDA
approval once patent infringement litigation is initiated.

Reps. Henry Waxman (D-Calif.), chairman of the House Energy and Commerce
Committee, Frank Pallone (D-N.J.), chairman of the Energy and Commerce
Subcommittee on Health, Nathan Deal (R-Ga.) and Jo Ann Emerson (R-Mo.)
introduced the legislation Wednesday. Two competing bills are expected to be
introduced in the House this week (DID, Feb. 26).

The bill sets out the FDA’s requirements for determining whether a product is
interchangeable with the brand reference biologic. An abbreviated biological
product application (ABPA) would be filed for either a biosimilar or a
biogeneric, “notwithstanding minor differences in heterogeneity profile,
impurities or degradation patterns” to the reference product, according to the
bill.

A biologic is considered biosimilar if there is not a clinically meaningful
difference between it and its reference product. A biosimilar can be deemed
interchangeable with the reference biologic if “the patient can be switched one
or more times between the reference product and the biological product without
an expected increase in the risk of adverse effects, including a clinically
significant change in immunogenicity, or diminished effectiveness,” the bill
states.

The information that generic companies would be required to provide to the
FDA to have their product deemed interchangeable would be left to the HHS
secretary’s discretion — but it could include results from chemical, physical
and biologic assays, as well as clinical studies that are deemed not duplicative
or unethical, according to the bill.

Looking to Future

Sens. Charles Schumer (D-N.Y.), Susan Collins (R-Maine), Sherrod Brown
(D-Ohio), and David Vitter (R-La.) are expected to introduce a bipartisan
companion bill in the near future.

Amgen is expecting legislation for follow-on biologics to be enacted this
year, according to Amgen’s Chief Financial Officer Robert Bradway. But the
details regarding interchangeability and exclusivity still need to be hashed
out, he said Wednesday at the Barclay’s Capital Healthcare Conference.

The legislation would prevent the FDA from delaying the approval of an ABPA
because of a citizen petition and requires the agency to act on such
applications under a 10-month review clock.

Industry Reaction

The potential savings from biogenerics is huge, Teva Pharmaceutical
Industries says in a statement. “The average daily cost of a biologic product is
approximately 22 times greater than a traditional drug,” the company says. “A
2008 economic study found that a U.S. biogenerics market would both promote
competition and generate cost savings of just over $100 billion over the next 10
years.”

Debra Barrett, Teva vice president of government relations, told DID
Wednesday that the introduction of the bill is a momentous step and she is
hopeful about the prospects for passage of biogenerics legislation in the
Senate.

The company is very well positioned in biogenerics and has the manufacturing
capability for the products, as evidenced by European approval of its
biosimilars, she said. “We are ready to go,” Barrett said.

In response to the bill, PhRMA’s Senior Vice President Ken Johnson notes in a
statement that the bill falls short of promoting medical innovation.

“It will impede medical progress, which hurts patients who are waiting for
cures today and those who are looking for hope in the future,” Johnson says. “It
will chill investment in the biotechnology sector, which continues to be the
source of high-quality, science-based jobs and a major contributor to our
economic recovery.”

FOB Companies May Spend $40 Million on Patent Disputes

Developers of follow-on biologics (FOBs) are likely to spend a total of as
much as $40 million defending themselves against patent infringement lawsuits
filed by innovator companies, an expert said.

Innovators will be able to file more complex litigation against FOB
developers that would involve as many as 30 or 40 patents per biologic compared
with the usual four patents brand companies assert against generic-drug makers,
Jim Doyle said at a Center for Business Intelligence conference on FOBs
Wednesday. Doyle is a partner at Axinn, Veltrop & Harkrider LLP whose work
includes patent law.

Without a database like the FDA’s Orange Book,
innovators may be able to conceal their arsenal of patents better, Doyle said.
Because of the complex nature of biologics, innovators can often obtain a range
of patents covering the R&D, manufacturing, method of use and other aspects
of a product. As a result, FOB developers will spend a lot of money upfront
researching what patents innovators own that may be used against them.

In addition, FOB developers face further risks because of the number of third
parties that could take part in the litigation — for example, universities with
which an innovator may have a product-licensing agreement.

Another consideration FOB companies will have to take into account is the
potential for a 30-month stay of approval during a patent dispute. If there is
such a stay, as has been the case with small-molecule drugs, litigation costs
will soar, influencing a company’s legal strategy, Doyle added (See related story.)

FOB companies also will have to pay for biologics experts to offer testimony
during trial. There may not be enough of them at first because of the technical
expertise involved.

High costs may encourage companies to settle, but they must consider such
factors as the remaining period of data exclusivity an innovator has for a
product, the market size for the biologic and the merits and strength of the
lawsuit, Doyle said. — Elizabeth Jones

Sepracor Settles Xopenex Patent Litigation With Barr, Teva

Sepracor will allow Teva Pharmaceuticals USA and its Barr Laboratories
subsidiary to market generic versions of Sepracor’s inhaled respiratory drug
Xopenex as part of a settlement of a patent infringement lawsuit.

Sepracor’s Xopenex (levalbuterol HCl) is used to treat reversible obstructive
airway disease. The settlement will result in the dismissal of Sepracor Inc.
v. Barr Laboratories, Inc., which was filed in July 2007 in the U.S.
District Court for the District of Delaware.

Teva and Barr will be able to sell the generic versions under a nonexclusive
license beginning Feb. 17, 2013, or earlier under certain conditions. When the
companies start marketing the drug, they will pay Sepracor a
royalty.

“We are very pleased with the resolution of our patent
infringement dispute with Barr and patent issues with Teva, as it allows all
parties to avoid the uncertainties and expenses related to patent litigation,”
Adrian Adams, Sepracor’s president and CEO, says in a statement.

Sepracor says it is still suing Dey for infringing on the Xopenex patent with
its generic version of the drug, in a case filed in the U.S. District Court for
the District of Delaware in February 2006.

Teva did not respond to requests for comment by press time. — Martin Gidron

FDA Gets $2.6 Billion in Appropriations Bill Signed by President

The Fiscal Year (FY) 2009 Omnibus Appropriations Act was signed into law by
President Barack Obama, giving $2.6 billion to the FDA.

The Senate passed the bill,H.R. 1105, Tuesday. It maintains all of
the FDA funding designated in the House version. (DID,
Feb.
26)

The funding, which applies to the entire fiscal year, includes $2 billion in
direct appropriations to the FDA. That represents an increase of $325 million,
or almost 20 percent, above the FY 2008 level, a congressional staffer told
DIDafter the House approved the bill last month.

About $41 million of the $777 million appropriated for CDER and related field
activities in the Office of Regulatory Affairs (ORA) will go to the Office of
Generic Drugs. CBER and related activities in the ORA will get $271 million.

The measure also authorizes the FDA to collect about $511 million in
prescription drug user fees, $53 million in device user fees and $20 million in
animal drug user fees.

In a move designed to replace funding the FDA would have received if it were
authorized to collect user fees for direct-to-consumer advertising, the
monitoring will receive about $6.6 million of direct appropriations.

Senators from both parties criticized earmarks in the bill. Sen. John McCain
(R-Ariz.) led the opposition against several of the spending measures in the
bill, such as funding for a trolley in Puerto Rico.An amendment offered
by McCain eliminating several of the spending provisions was defeated in the
Senate by a 62–39 vote Monday.

The bill ultimately received the backing of a handful of Republicans, who
supported a cloture motion that subsequently led to the final passage of the
bill on a voice vote.

Obama acknowledged the earmarks in a White House statement, calling the bill
imperfect but necessary for the government to continue functioning.

FDA: Researcher Enrolled Patients Before Getting Lab Results

A clinical investigator enrolled all his patients in a drug trial before
getting required lab results, the FDA says in a warning letter.

In some instances, Virendra Desai of the Physician Alliance Research Center,
Hawaiian Gardens, Calif., did not receive and review lab results for up to 20
days after the subjects were infused intravenously with the drug in the Phase
III clinical trial. His actions may have compromised their safety, according to
the warning letter posted to the FDA website this week.

The FDA rejected Desai’s explanation that the study protocol only indicated
that central laboratory testing needed to be obtained because a different page
of the protocol stated that all screening and pre-dose assessments were to be
considered as baseline and had to be performed and reviewed before the first
day’s randomization and dosing.

Desai enrolled a subject with elevated liver function test results and a
history of alcohol abuse in violation of the patient enrollment criteria and
gave the subject five doses of the study drug before the problem was detected
and the patient was dropped from the trial.

The FDA says the investigator also failed to complete a pregnancy test for a
female subject before she received the study drug. The investigator did not
conduct a physical exam, wound assessment and overall clinical assessment since
baseline for another subject by the eighth day of the study as the protocol
required, according to the warning letter, which was based on an inspection the
FDA conducted March 17 through April 17, 2008.

Desai was cited for not maintaining adequate and accurate case histories. For
example, the warning letter says, there were numerous instances in which subject
data or the nurse’s notes were changed without dates or the initials of the
person making the change, with the apparent intention of matching the times on
the case report forms. This made it difficult to accurately determine when the
drug was administered for five of his 18 subjects.

The FDA cited Desai for considering subjects cured without adequate
documentation, a determination he said was based on his own judgment. “We
acknowledge your explanation and remind you of the importance of adequate and
accurate documentation of events,” the warning letter says.

The investigator is cited for drug disposition record errors, including
“numerous discrepancies between … dispensing records kept by the unblinded
pharmacy and what was recorded on the drug accountability forms” for several
subjects in both the treatment and placebo arms of the study, several instances
in which the same kit was dispensed to different subjects and numerous
discrepancies between the nurse’s notes and what was recorded on corresponding
forms regarding doses of study medication.